J Cardiol 2007 Feb; 49（2）: 63 – 67

Possible Predictors of Target Lesion
Revascularization After DrugEluting Stent Implantation
Daizaburo YANAGI, MD
Kazuyuki SHIRAI, MD
Ken MORI, MD
Amane IKE, MD
Costantino O.

COSTANTINI, MD＊1

Costantino R.

COSTANTINI, MD＊1

Hiroaki NISHIKAWA, MD
Nathan MILLER
Bo ZHANG, MSYoshihiro TSUCHIYA, MD＊2
Hidenori URATA, MD＊2
Keijiro

SAKU, MD, FJCC

Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Background. A small number of patients still need target lesion revascularization（TLR）
after drug-eluting stent（DES）implantation. It is important for the management of coronary artery disease to assess thepredictors of TLR after DES implantation.
Methods and Results. Two hundred ninety-seven patients（325 lesions）were treated with CypherTM
sirolimus-eluting and/or TAXUSTM paclitaxel-eluting stent implantation at four centers in Japan and Brazil.
Among these centers, 20 patients（24 lesions）needed clinically driven TLR. The clinical and angiographic
characteristics of TLR patients were compared to those of non-TLR patients. Hemodialysis, prior myocardial infarction（MI）and prior coronary artery bypass grafting（CABG）
were more frequent in TLR patients
than in non-TLR patients. An ostial stenosis was more frequent in the TLR group than in the non-TLR
group（41.7% vs 19.9%, p＝0.012）. In addition, post-procedure in-stent percentage diameter stenosis（%DS）was higher in TLR patients（21.9% vs 13.3%, p ＝ 0.002）. Stepwise logistic regression analysis
indicated that all of these variables were independent predictors of TLR after DES implantation.
Conclusions. Hemodialysis, prior MI, prior CABG, ostial lesion location and high in-stent %DS may be
independent predictors of TLR after DES implantation.
──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2007 Feb; 49（2）: 63−67

Key Words
Stent drug-eluting

Revascularization

INTRODUCTION（SES）andBoth CypherTM sirolimus-eluting stent（PES）have been
TAXUSTM paclitaxel-eluting stentproven to reduce restenosis after percutaneous
coronary intervention（PCI）
and to improve the clinical outcome in patients with PCI in many clinical
trials.1−3）However, a small number of patients still──────────────────────────────────────────────
福岡大学医学部 第二内科 : 〒 814−0180 福岡市城南区七隈 7−45−1 ; ＊1Clinica Cardiologico C. Costantini, Curitiba, Brazil ; ＊2 福岡大学筑紫病院 第一内科，福岡
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka ; ＊1Clinica Cardiologico C. Costantini, Curitiba, Brazil ;＊2
The First Department of Internal Medicine, Fukuoka University Chikushi Hospital, Fukuoka
Address for correspondence : SAKU K, MD, FJCC, Department of Cardilogy, Fukuoka University School of Medicine, Nanakuma 7−
45−1, Jonan-ku, Fukuoka 814−0180 ; E-mail : saku-k@cis.fukuoka-u.ac.jp
Manuscript received November 29, 2006 ; revised December 12, 2006 ; accepted December 13, 2006

63

64

Yanagi, Shirai, Mori et al

experience restenosis after SES or PES implantation and require target lesion revascularization（TLR）. Although some factors such as diabetes,
long lesion or small vessel4,5） are well known topredict TLR after bare metal stent（BMS）
implantation, such predictors after drug-eluting stent（DES）
implantation have not yet been clarified. The purpose of this study was to identify possible predictors of TLR after DES implantation and to clarify
their possible significance in the management ofcoronary artery disease.
SUBJECTS AND METHODS
Study design
Consecutive patients who had been treated withSES or PES and who had more than 6 months ofclinical follow-up at the Clinica Cardiologico C.
Costantini（Curitiba, Brazil）between May 2003 andJune 2004, or at Fukuoka University Hospital,
Fukuoka University Chikushi Hospital and White
Cross Hospital between August 2004 and July
2005, were enrolled in this study. Clinical characteristics, lesion characteristics, interventional procedure and clinical events were compared between
20 patients（24 lesions）with TLR（TLR group）and
277 without TLR（non-TLR group）
in a total of 297
patients（192 SES, 134 PES）with 325 lesions toevaluate the predictors of TLR after DES implantation. Patients with acute myocardial infarction（MI）
within 24 hr after the onset were excluded from thisstudy. Clopidogrel or ticropidine was prescribed forat least 6 months. Clinical follow-up information
was obtained by telephone contact or by reviewing
hospital records. During follow-up, coronary
angiography was performed only as clinically indicated in Brazil and routinely in Japan. TLR was
basically performed when the percentage diameter
stenosis（%DS）of the target lesion was more than
50 and myocardial ischemia was documented in thetarget vessel area by a noninvasive method. AcuteMI was defined by a rise in the creatine kinase levelof more than twice the upper normal limit with anincreased creatine kinase-MB or Troponin-T. This
study was approved by the ethics committee of
Fukuoka University Hospital.
The angiographic laboratory at Fukuoka
University Hospital analyzed all procedural andpost-procedural angiographic images using CMSGFT（MEDIS）. The angiographic laboratory wasunaware of the treatment assignment. All measurements were performed on angiographic images

recorded after the intracoronary administration of
nitroglycerin. The target lesion was defined as thestent and 5 mm proximal and distal to the edge ofthe stent. Ostial lesions were those that began within 3 mm of the major epicardial artery ostium.
Statistical analysis
All statistical analyses were performed using theSAS（ Statistical Analysis System）Software
Package（Version 9.1, SAS Institute）at Fukuoka
University. The distribution of variables was examined by the Shapiro-Wilk test. Differences in categorical variables between the TLR and non-TLR
groups were examined by the chi-square test.
Differences in continuous variables between the
TLR and non-TLR groups were examined byanalysis of variance and/or the Wilcoxon rank-sum
test. Correlations between variables were examinedby the Spearman correlation. Stepwise multiple
regression analysis was used to examine the independent variables that predicted TLR. The significance of the variables that predicted TLR after controlling for other related variables was examined bymultivariate logistic regression analysis using
dummy variables. The odds ratio and 95% confidence interval are given. All p values are twotailed. The significance level was considered to be
5% unless indicated otherwise.
RESULTSClinical and lesion characteristics
The mean follow-up period in all patients was
174.6 ± 72.7days. There was no death and （0.4%）
1
MI because of stent thrombosis during this period（Table 1）. Baseline patient characteristics areshown in Table 2. There were no significant differences in age or the incidence of male or diabetic
patients between the TLR and non-TLR groups.
The prevalences of prior MI, prior coronary artery
bypass grafting（ CABG）and hemodialysis werehigher in the TLR group than in the non-TLR
group（60.0% vs 27.5%, p ＝ 0.004, 45.0% vs
18.7%, p ＝ 0.009, 8.3% vs 0.7%, p ＝ 0.028,
respectively）. Although lesion length in the TLR
group was greater than that in the non-TLR group,
this difference was not statistically significant.
Ostial stenosis was more frequent in the TLR groupthan in the non-TLR group（41.7% vs 19.9%, p ＝0.012 ; Table 3）.

J Cardiol 2007 Feb; 49（2）: 63 – 67

65Target Lesion Revascularization After DES Implantation

Table 1

Overall clinical events

Table 4After discharge

In hospital

Follow-up period（days）

Procedural results
TLR group Non-TLR group p value（n＝24） （n＝301）

174.6±72.7

Death

0

0

MLD
（insegment）（mm） 1.8±0.4

2.0±0.6NSMI

01（0.4%）

Final MLD
（instent）（mm）2.2±0.5

2.5±0.5＜0.01

TLR PCI

020（6.7%）

Stent %DS final（%）

21.9

13.3

0.002

TLR CABG

1（0.4%）

0%DS final（%）

26.7

24.2

＜0.01

Stent thrombosis

1（0.4%）

1（0.4%）%DS proximal edge（%）

17.1

14.9

NS

%DS distal edge（%）

20.4

18.7

NS

Stent length（mm）

30.8±15.4

24.0±10.0

0.012

MI＝myocardial infarction ; TLR＝target lesion revascularization ; PCI＝percutaneous coronary intervention ;CABG＝coronary artery bypass grafting.

Table 2

Stent/lesion ratio

1.3±0.4

1.6±0.7

NS

Balloon/artery ratio

1.56±0.38

1.49±0.51

NS

Continuous values are mean±SD.
Abbreviations as in Tables 1, 3.

Clinical characteristics
TLR group Non-TLR group p value（n＝20） （n＝277）

Table 5
65±11

63±11

NS

Male（%）

90

77.8

NS

DM（%）

35.0

23.8

NS

HT
（%）

85.0

68.7

NS

HL（%）

60.0

70.6

NS

UAP
（%）

25.0

29.1

Prior MI（%）

60.0

Age（yr, mean±SD）

Odds ratio（95% CI）

p value

Prior MI

3.5（1.3−9.1）＜0.01

Hemodialysis

2.9（1.0−8.3）

＜0.05

NS

Prior CABG

2.8（1.1−7.5）

＜0.05

27.5

0.004

Ostial location

2.6（1.1−6.3）＜0.05

Final %DS
（in stent）

3.1（1.2−8.2）＜0.05

Prior CABG
（%）

45.0

18.7

0.009

HD（%）

8.3

0.7

0.028

DM＝ diabetes mellitus ; HT＝hypertension ; HL＝hyperlipidemia ; UAP＝unstable angina pectoris ; HD＝hemodialysis.
Other abbreviations as in Table 1.

Table 3

Lesion characteristics
TLR group Non-TLR group p value（n＝24） （n＝301）

Ostial lesion
（%）

41.7

19.9

0.012

ISR（%）

25.0

21.3

NS

Bifurcation
（%）

66.8

48.3

NS

SVG graft（%）

8.3

2.0

NS

Multivessel disease（%）

65.0

62.4

NS

Type B2 / C lesion（%）

87.5

71.4

NS

Brush grade （
3 %）

66.7

70.0

NS

Lesion length（mm）

21.8±13.6

17.1±9.6

NS

Reference（mm）

2.6±0.7

2.7±0.6

NS

MLD pre（mm）

1.0±0.7

1.0±0.4

NS%DS pre（%）

63.0

62.8

NS

Continuous values are mean±SD.
ISR＝in-stent restenosis ; SVG＝saphenous vein graft ;MLD＝minimum lumen diameter ; %DS＝percentage diameter
stenosis. Other abbreviation as in Table 1.

J Cardiol 2007 Feb; 49（2）: 63 – 67

Multivariate predictors of target lesion revascularization

CI＝confidence interval. Other abbreviations as in Tables 1, 3.

Procedural results（Table 4）
Stent length was greater in the TLR group thanin the non-TLR group（30.8 ± 15.4 vs 24.0 ±10.0 mm, p ＝ 0.012）, whereas the stent / lesion
length ratio was not significantly different between
the two groups. After the procedure, in-stent %DS
in the TLR group was higher than that in the nonTLR group（21.9% vs 13.3%, p ＝ 0.002）. Among 8
TLR lesions with ostial lesion treatment, the ostium
was fully covered by DES in 7 lesions. Eighteen
TLR lesions in Japanese patients were completely
followed by angiographic analysis, which showed
restenosis in 8 focal body lesions, 8 marginal
lesions and 2 multifocal lesions. One of thesepatients suffered stent fracture.
Predictors of TLR（Table 5）
Stepwise multiple regression analysis indicatedthat hemodialysis, prior MI, prior CABG, ostial
lesion, and post-procedural %DS were independent
predictors of TLR, and these variables were interdependent by multivariate logistic regression analy-

66

Yanagi, Shirai, Mori et alsis. As shown in Table 5, patients with prior MI
were associated with about a 3.5-fold higher risk of
TLR compared to those without prior MI.
Hemodialysis was associated with about a 2.9-foldhigher relative risk of TLR.
DISCUSSION
Both SES and PES have been shown to drastically reduce restenosis and TLR after PCI. The extent
of neointimal hyperplasia after SES or PES implantation is known to be different between the two
types of DESs because of the different types ofdrugs and polymers. However, the mechanism bywhich restenosis is reduced is similar between the
two DES methods ; negative remodeling is prevented by the metal stent and neointimal hyperplasia issuppressed by the anti-proliferative agents. Thus,
we analyzed combined SES and PES data to determine the predictors of TLR. The TLR rate for SES
9 months after PCI was 4.1% in the SIRIUS trial3）
and that for PES was 3.0% in the TAXUS-Ⅳ trial.1）
In the present study, the TLR rate at 6 months after
DES implantation was 7.4%, which was higher
than in the SIRIUS and TAXUS-Ⅳ trials. However,complex clinical and lesion characteristics such as
renal failure, left ventricular dysfunction, small
vessel or long lesions were excluded in both SIRIUS and TAXUS IV trials. In contrast, in this study,
we enrolled most patients except those with acute
MI. Thus, the possible reason of higher incidenceof TLR in this study is that patients with complex
clinical and lesion characteristics were included.
Although some factors such as diabetes mellitus,
long lesion, small reference vessel, ostial lesion
location or small final minimum lumen diameter
have been reported to be predictors of TLR after
BMS implantation,4,6,7）it is unclear whether thesefactors can also predict TLR after DES implantation. In the present study, hemodialysis was identified as one of the predictors. Stent under-expansion
seems to be more frequent in hemodialysis than in
non-hemodialysis patients because of the more
intense coronary artery calcification in hemodialysis patients.8,9）Two of 14 TLR lesions in patientswith prior CABG were in saphenous vein grafts.
Although it is not clear why restenosis is frequentin patients with prior CABG or prior MI, one of thepossible reasons is that these patients had more

severe atherosclerosis compared to those without
such conditions. Meanwhile, diabetes mellitus was
not a predictor of TLR which showed intensely
suppressed neointimal hyperplasia with DES. Thus,a possible mechanism of restenosis may be unfavorable stent expansion rather than neointimal
hyperplasia. In fact, smaller final %DS was also a
possible predictor of TLR in our study.
One of the Japanese TLR cases showed stent
fracture at follow-up coronary angiography. Ostial
lesions are known to have high rates of restenosis
after bare metal stent implantation because of thetechnical difficulty of accurate stent positioning andthe high elasticity of the ostium : 10,11）7 of 8 ostial
lesions with TLR were completely covered by
DES. Stent under-expansion just after the procedure was seen in one patient. Mechanical problems
such as chronic recoil rather than neointimal hyperplasia might be important in ostial restenosis. DES
with higher radial force might be effective for thetreatment of ostial lesions.
Study limitations
The most important limitation of this study is thenumber of patients. Since the incidence of TLR
after DES implantation is low, there is a limitation
with the number of patients in this study to statistically identify predictors of TLR after DES implantation. Instead, we observed each patient with TLR
in detail. Another limitation of this study is thedifference in the follow-up methodology :angiographic follow-up was performed in mostpatients in Japan whereas only clinical follow-up
was performed in Brazil. However, the determination of TLR was also clinically driven in Japan.
The difference in race between the two countries
does not seem to be a big issue for identifying predictors of TLR because the two groups are thought
to have a similar mechanism of restenosis after
DES implantation.
CONCLUSIONS
Hemodialysis, prior MI, prior CABG, ostial
lesion location and small in-stent %DS are possible
predictors of TLR after DES implantation. A possible mechanism of restenosis could be unfavorable
stent expansion.

J Cardiol 2007 Feb; 49（2）: 63 – 67

Target Lesion Revascularization After DES Implantation

要

67

約

薬物溶出性ステント留置後の再血行再建術施行予測因子の検討
柳

大三郎

白井

和之

コスタンティニ
ミラー・ネイサン
背

森

憲

池

周 而

コスタンティノ R. コスタンティニ
張

波

土屋

芳弘

浦田

コスタンティノ O.
西川
秀則

宏明
朔

啓二郎

景 : 薬剤溶出性ステント（DES）留置後に標的病変再血行再建（TLR）を必要とする症例を少数例ではあるが経験する．TLR の予測因子を検討することは，虚血性心疾患の治療方針を決定する
うえで重要である．
方法と結果 : 日本とブラジルの 4 施設において 297 例の患者（325 病変）に対して CypherTM シロリ
ムス溶出性ステントまたは TAXUSTM パクリタキセル溶出性ステントが留置された．これらのうち
20 例（24 病変）は，臨床的に TLR が必要であった．今回我々は TLR を要した患者群とそうでなかった患者群の間で，患者背景，病変背景を比較検討した．その結果，TLR 群では透析患者，心筋梗
塞および冠動脈バイパス術の既往のある患者が非 TLR 群に比べて多かった．また TLR 群では，非TLR 群に比べて入口部病変が多く認められ（41.7% vs 19.9%, p ＝ 0.012），さらには手技後のステント内径狭窄率が高値であった（21.9% vs 13.3%, p ＝ 0.002）．多変量解析の結果，これらの因子はDES 留置後の TLR の独立した予測因子であった．
結論 : 透析，心筋梗塞および冠動脈バイパス術の既往，入口部病変と術後にステント内径狭窄率が高いことは，DES 留置後 TLR の予測因子となりうる可能性が示唆される．

J Cardiol 2007 Feb; 49（2）: 63−67

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